mRNP assembly, axonal transport, and local translation in neurodegenerative diseases

Abstract

The development, maturation, and maintenance of the mammalian nervous system rely on complex spatiotemporal patterns of gene expression. In neurons, this is achieved by the expression of differentially localized isoforms and specific sets of mRNA-binding proteins (mRBPs) that regulate RNA processing, mRNA trafficking, and local protein synthesis at remote sites within dendrites and axons. There is growing evidence that axons contain a specialized transcriptome and are endowed with the machinery that allows them to rapidly alter their local proteome via local translation and protein degradation. This enables axons to quickly respond to changes in their environment during development, and to facilitate axon regeneration and maintenance in adult organisms. Aside from providing autonomy to neuronal processes, local translation allows axons to send retrograde injury signals to the cell soma. In this review, we discuss evidence that disturbances in mRNP transport, granule assembly, axonal localization, and local translation contribute to pathology in various neurodegenerative diseases, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD).

Keywords: ALS; Axonal transport; Local translation; SMA; mRNA transport; mRNP assembly.

Figure 1. mRNP assembly, axonal transport, and local translation defects in SMA

SMA is caused by deletions or mutations in the SMN1 gene locus, leading to reduced SMN protein levels. SMN deficiency causes reduced assembly of mRNAs (e.g. β-actin, Gap-43, Nrn1) and mRBPs (e.g. HuD and IMP1) into mature mRNA transport granules, and decreased axonal transport of mRNPs. This impairs mRNA localization and translation at axon terminals, causing synaptic defects at NMJs.

Figure 2. mRNP assembly, axonal transport, and local translation defects in ALS/FTD

An important hallmark of ALS/FTD pathology is the loss of TDP-43 or FUS mRBPs from the nucleus, and their accumulation in cytoplasmic aggregates. This defect is associated with, and perhaps triggered by reduced nuclear protein import through nuclear pore complexes (NPCs), which in turn further contribute to nucleocytoplasmic transport defects. The most common form of fALS is caused by GGGGCC hexanucleotide repeat expansions in the first intron of the C9orf72 gene locus, leading to the accumulation of nuclear RNA foci and DPR aggregates formed by RAN translation. These TDP-43 or FUS aggregates, as well as nuclear RNA foci and DPR aggregates, can trap mRNAs and mRBPs, impairing the assembly and transport of mRNA transport granules in axons. Affected transcripts include those encoding Neurofilament-L and MAP1B. This deficiency causes reduced local translation at axon terminals, leading to instability of microtubules (MTs) and synaptic defects.

Figure 3. Transmission of a neurodegenerative signal from axon to the cell body in AD

Aggregates of oligomeric Aβ_1-42 trigger, via a currently unknown signaling mechanism, an increased anterograde transport of specific mRNAs from the cell soma into axon terminals. One of these mRNA encodes the transcription factor ATF4 that is locally translated. A locally assembled signaling complex containing ATF4 is retrogradely transported to the cell soma, where it enters the nucleus and induces the expression of the transcription factor CHOP, causing cell death.